Myofibroblasts are reparative connective tissue cells that contribute to the reconstruction of injured tissue by secreting new extracellular matrix and by exerting high contractile force. Deregulation of these activities results in tissue contracture and development of fibrosis which makes the myofibroblast an important target for anti-fibrotic therapies. Two principle factors drive the development of myofibroblasts from different precursor cells and guarantee maintenance of the contractile phenotype: mechanical stress and transforming growth factor beta (TGFbeta1). In this mini-review, we recapitulate the current understanding (1) of how myofibroblasts feel stress using specialized matrix adhesions, (2) of the level of stress that is required to induce their development and (3) of how myofibroblast mechanical activity can have a direct influence on the level of TGFbeta1 activation. From these findings it emerges that the specific matrix adhesion structures of myofibroblasts are promising targets to modulate myofibroblast differentiation and activity.